Donor interleukin-4 promoter gene polymorphism influences allograft rejection after heart transplantation.

BACKGROUND: The cytokine interleukin-4 (IL-4) is secreted mainly by activated T lymphocytes and characterizes the T-helper 2 (Th2) sub-type. In transplantation Th2 cells are believed to induce graft tolerance. Previous studies revealed that patients with a relatively high frequency of IL-4 producing helper T lymphocytes (HTL) before heart transplantation (HTX) had no or less rejection episodes compared with patients with a low frequency of IL-4 producing HTL. Three single nucleotide polymorphisms (SNPs) have been identified in the promoter region of the IL-4 gene, which influence promoter strength. We investigated whether there was a correlation between SNP genotypes in the IL-4 promoter and heart failure, and rejection after HTX. METHODS: Seventy HTX patients, 61 donors, and 36 controls were genotyped for the 3 SNPs by sequencing. RESULTS: Of the SNPs at -285 and -81, only the C and A alleles, respectively, were found in this study. Both alleles were found for the -590 SNP. No relation between patient genotype of the SNP at -590 and heart failure and rejection was found. However, incidence of rejection was significantly lower in patients that received a donor heart with the T-positive genotype compared with patients that received a heart from a T-negative donor. Patients who had the T-negative genotype and received a heart from a T-positive donor, suffered significantly less from rejection than T-negative patients that received a T-negative donor heart. This was not significant in the T-positive patient group. CONCLUSIONS: This indicates that IL-4 production within the donor heart and by cells from the donor is important for reducing incidence of episodes of rejection.     

Characterization of P-glycoprotein and multidrug resistance proteins in rat kidney and intestinal cell lines.

The activity of P-glycoprotein (Pgp/MDR1/ABCB1) and multidrug resistance proteins (MRP/ABCC) influence the pharmacokinetics and bioavailability of many drugs. Few suitable cell lines for the study of drug transport exist. Additional non-human cell lines may help clarify species differences and contribute to the current knowledge of drug transport. The aim of the present study was to characterize three rat epithelial cell lines for transporter expression and activity. Transporter expression was assessed in intestinal IEC-6 and renal GERP and NRK-52E cells using RT-PCR and Western blot analysis. Pgp and Mrp transport activity were analyzed by measuring calcein accumulation and glutathione-S-bimane efflux, respectively. The three cell lines showed Pgp expression and Pgp-dependent transport, both decreasing with culture time after reaching confluency. Besides Pgp, cells expressed Mrp1, Mrp3, Mrp4, and Mrp5, while Mrp2 and Mrp6 were absent. In addition, they showed temperature- and Mrp-dependent efflux of glutathione-S-bimane. Exposure to a panel of different inhibitors showed that this efflux was probably mediated by Mrp4. In conclusion, the three rat epithelial cell lines investigated showed Pgp and Mrp expression and transport. Mrp dependent transport was most likely mediated by Mrp4. In future, these cell lines may be used as in vitro models to study drug transport.     

Stress proteins as inducers and targets of regulatory T cells in arthritis

Immunization with microbial or mammalian stress proteins or heat-shock proteins in models of experimental autoimmunity has been observed to lead to increased disease resistance. Furthermore, such immunization has been proposed to result in the induction and expansion of T cells that suppress disease upon transfer. Comparisons of microbial heat-shock proteins with other conserved immunogenic proteins of bacterial origin have indicated a unique capacity for heat-shock proteins to induce a regulatory phenotype in T cells, such as reflected by the production of IL10. Also, studies in children with chronic arthritis have indicated that T-cell responses to heat-shock proteins are associated with a benign course of the disease and with remission. Furthermore, in patients, heat-shock-protein-(HSP-) activated T cells were shown to display regulatory phenotypes consistent with CD4+ CD25+ T regulatory cells.     

Inability to Work Fulltime,Prevalence and Associated Factors Among Applicants for Work Disability Benefit

Journal of Occupational Rehabilitation - Purpose Inability to work fulltime is an important outcome in the assessment of workers applying for a disability benefit. However, limited knowledge is...     

Radiomics for the Prediction of Treatment Outcome and Survival in Patients With Colorectal Cancer: A Systematic Review

Prediction of outcome in patients with colorectal cancer (CRC) is challenging as a result of lack of a robust biomarker and heterogeneity between and within tumors. The aim of this review was to assess the current possibilities and limitations of radiomics (on computed tomography [CT], magnetic resonance imaging [MRI], and positron emission tomography [PET]) for the prediction of treatment outcome and long-term outcome in CRC. Medline/PubMed was searched up to August 2020 for studies that used radiomics for the prediction of response to treatment and survival in patients with CRC (based on pretreatment imaging). The Quality Assessment of Diagnostic Accuracy Studies (QUADAS) tool and Radiomics Quality Score (RQS) were used for quality assessment. A total of 76 studies met the inclusion criteria and were included for further analysis. Radiomics analyses were performed on MRI in 41 studies, on CT in 30 studies, and on ¹⁸F-FDG-PET/CT in 10 studies. Heterogeneous results were reported regarding radiomics methods and included features. High-quality studies (n = 13), consisting mainly of MRI-based radiomics to predict response in rectal cancer, were able to predict response with good performance. Radiomics literature in CRC is highly heterogeneous, but it nonetheless holds promise for the prediction of outcome. The most evidence is available for MRI-based radiomics in rectal cancer. Future radiomics research in CRC should focus on independent validation of existing models rather than on developing new models.     

Survival and Health-Related Quality of Life after Hospitalization for Necrotizing Soft Tissue Infections of the Upper Extremity: A Long-Term Outcome Study

Introduction  The main aim of the study was to investigate the survival and health-related quality of life (HRQoL) after hospitalization for necrotizing soft tissue infections (NSTIs) of the upper extremity. Materials and Methods  A retrospective study with long-term follow-up of patients surviving NSTIs of the upper extremity was performed. Survival and HRQoL after hospital discharge were the primary outcomes. The HRQoL was measured using the 36-item Short Form (SF-36), EuroQoL-5D-5L (EQ-5D), Quick Disability of Shoulder, Arm and Hand (QuickDASH), and numeric rating scales (NRS) for satisfaction with appearance and pain. Results  A median of 6.5 years after hospitalization, 81% of the 108 patients survived. The response rate was 45% ( n = 38). The SF-36 score was 80 (interquartile range [IQR]: 58–91), the EQ-5D score 1.4 (IQR: 1.2–2.2), the EuroQoL-Visual Analog Scale score 77 (IQR: 67-90), the QuickDASH score 13.6 (IQR: 2.3-30.7), the NRS for satisfaction with appearance 8 (IQR: 7–9), and NRS for pain 1 (IQR: 0-5). Conclusion  Six-and-a-half years after the NSTI, 81% of the patients were still alive. General health prior to the NSTI mainly influenced the risk at secondary mortality. In surviving patients, the HRQoL varied widely, but was adversely affected by female sex, intravenous drug use, NSTI type I or III, and longer length of hospital stay.     

Benefits and Burdens of Using a SNP Array in Pregnancies at Increased Risk for the Common Aneuploidies

We present the nature of pathogenic SNP array findings in pregnancies without ultrasound (US) abnormalities and show the additional diagnostic value of SNP array as compared with rapid aneuploidy detection and karyotyping. 1,330 prenatal samples were investigated with a 0.5‐Mb SNP array after the exclusion of the most common aneuploidies. In 2.7% (36/1,330) of the cases, pathogenic chromosome aberrations were found; a microscopically detectable abnormality in 0.7% and a submicroscopic aberration in 2%. Our results show that in addition to the age‐ or screening‐related aneuploidy risk, in pregnancies without US abnormalities, there is a risk of 1:148 (9/1,330) for a (sub)microscopic abnormality associated with an early‐onset often severe disease, 1:222 (6/1,330) for a submicroscopic aberration causing an early‐onset disease, 1:74 (18/1,330) for carrying a susceptibility locus for a neurodevelopmental disorder, and 1:443 (3/1,330) for a late‐onset disorder (hereditary neuropathy with liability to pressure palsies in all three cases). These risk figures are important for adequate pretest counseling so that prospective parents can make informed individualized choices between targeted prenatal testing and broad testing with SNP array. Based on our results, we believe if invasive testing is performed, SNP array should be the preferred cytogenetic technique irrespective of the indication.